Perhaps one of the most important and worrying studies into antibiotic resistance has just been published in The Lancet. It heralds the end of the antibiotic era…yes yes there has been talk of it for a while but it is NOW HERE...I see you think I’m being melodramatic so read on…

Imagine the scenario of a thirty year old lady with pyelonephritis. Over the past few days she has had worsening loin pain and is now septic with a high fever and rigors. On admission she is fluid resuscitated, started on IV Piptazobactam and given a stat dose of IV Gentamicin as per the hospital empirical antibiotic guidelines. Despite this she remains septic so she is changed to IV Meropenem. The next day the Microbiologists start to get anxious; her blood cultures grow a Meropenem resistant Escherichia coli. The Microbiologist recommends changing the patient to the last line of antibiotics: IV Colistin PLUS IV Amikacin. Despite all of the doctors best efforts this young lady, who has never been in hospital before, dies the following day from uncontrolled sepsis. Later the E. coli from her blood cultures is shown to be resistant to every antibiotic tested! There was simply no effective antibiotic treatment available. Does this sound like an unlikely doomsday scenario? Maybe we need to think again?

A team in China undertaking routine surveillance for various resistant bacteria in food animals discovered a higher than expected rate of Colistin resistant E. coli. This was surprising because Colistin resistance normally occurs by spontaneous mutation in a single bacterium which then cannot sustain this resistance because there is a survival cost to the bacterium i.e. having the resistance is burdensome to the bacterium so it reverts back to being sensitive. Usually the resistance is no longer required and it is better for the bacteria to no longer be resistant.

So what has changed? Well this time the resistance genes are on a plasmid, a mobile genetic element, which has been called MCR-1. This means that the resistance can now spread between bacteria rather than just being expressed by the one bacterium that happened to become resistant. Not only can this plasmid spread but the resistance appears to be stable so that once the bacterium has become resistant it stays resistant; it doesn’t need to revert to sensitive again when the selective pressure, in this case, Colistin, is removed. The researchers in China showed that the MCR-1 plasmid could easily transfer from E. coli to Klebsiella pneumoniae and Pseudomonas aeruginosa and once resistant these bacteria also stayed resistant.

So where was the resistance found and how common is it?The surveillance looked at 523 samples of raw meat (poultry and pigs) and found 78 (14.9%) contained E. coli resistant to Colistin by the MCR-1 gene. This was meat from retail sources e.g. supermarkets! They also looked at pigs from abattoirs and found these were also colonised with Colistin resistant E. coli 20.6% of the time.

These figures are terrifying enough but over the period of study the resistance to Colistin in retail meat has increased from 5.1% in 2011 to 24.4% in 2014… this kind of dramatic reproduction is what bacteria are very good at so these numbers are really scary!

Why has Colistin resistance occurred in animals?A great way of creating antibiotic resistant bacteria in food is to indiscriminately use antibiotics in animals and that is exactly what has happened here. China is the biggest poultry and pig producer in the world exporting millions of tonnes of meat to the rest of the world every year. China is also one of the world’s largest users of Colistin in animal husbandry. It’s no surprise then that China has a problem with Colistin resistant bacteria in food animals. However, we would be naive to think that the use of antibiotics in animals is only a Chinese problem. Europe imports nearly 500 tonnes of Colistin for use in animals every year; Colistin is used in fish farming as well as other food animal production. Why do this? ...because antibiotics make animals grow larger, faster and therefore make meat production cheaper!! It is highly probably that China is not the only source of Colistin resistant bacteria in the world, just the first to notice it.

Is MCR-1 confined to China?The researchers in China say that so far MCR-1 has only been found in China but there is no evidence that anyone else in the world has looked for it! Indeed, in the discussion the researchers say that other researchers in Malaysia appear to have found MCR-1 in E. coli but that confirmation is required. So MCR-1 may already have spread outside of China.

So what about human carriage of Colistin resistant bacteria?So far only a limited number of Colistin resistant bacteria due to MCR-1 have been found in humans. The study screened 1322 samples from patients and found 16 cases of MCR-1 positive bacteria (4 urine, 3 sputum, 3 unspecified drain fluids, 3 ascitic fluids, 2 bile and 1 wound). Clearly there has been animal to human transfer of bacteria or plasmids. The fact that MCR-1 has been found in humans at all is cause for concern. In a normal laboratory in the UK we do not routinely look for Colistin resistance therefore there could already be cases in the UK without us knowing. The researchers call for urgent surveillance to determine how far these bacteria have spread. I bet Colindale (the national reference laboratory) will replicate this study on all their E. coli isolates looking for MCR-1, we will then know if MCR-1 has actually arrived in the UK without detection. As for the speed of spread, ESBLs and carbapenem resistance occurred over approximately 5 years, the dissemination of MCR-1 is likely to be at least as rapid.

So what are the risk factors for infection and what impact will it have on clinical care?In truth the risk factors are yet to be determined. The assumption is that it will be the use of broad spectrum antibiotics; it may not need to be exposure to Colistin. Avoiding Colistin won’t necessarily prevent the spread of MCR-1 either. Let me explain, in an ideal world all bacteria would be sensitive and killed off by our antibiotics. However these are organisms and like anything under threat they evolve to survive. Bacteria use transposons and plasmids to gain resistance in order to survive. Bacteria with resistance on plasmids don’t tend to stop at one resistance mechanism; they collect multiple methods of resistance in order to better protect themselves from the onslaught of antibiotics.

​Essentially a plasmid is a weapons store for them to collect their armour, a helmet, a mace, an axe and a dagger or a sword etc. The plasmid allows the bacterium to contain many resistance mechanisms be it ESBL resistance to Beta-lactams, Aminoglycoside Modifying Enzyme resistance to Gentamicin, mutation in topoisomerase and DNA gyrase resistance to Ciprofloxacin, mutation in dihydrofolate resistance to Trimethoprim, or now MRC-1 resistance to Colistin. Prescribing any one of these antibiotics, say Ciprofloxacin, will kill off any other bacteria present which do not have that resistance mechanism, leaving behind the bacterium with the resistance mechanism, which because of the plasmid (its weapons store) is also carrying MCR-1.

This initial treatment may cure the patient this time however the next time they get an infection it will be with resistant bacteria (that’s all that was left behind, waiting for its opportunity). This may then be the infection that kills the patient as it is resistant to all antibiotics! Just as bacteria can then spread between people (hands, lack of cleaning, sneezing etc) the plasmid with its weapon armoury can transfer between bacteria, so sensitive Klebsiella spp. can meet an E. coli containing the plasmid and just as if they shook hands the plasmid is transferred by a pilus (appendage) to the Klebsiella spp., which is now a multi-resistant Klebsiella spp. The upshot for clinical care is now there are bacteria out there in the human population known to be carrying highly transferable resistance to our last line antibiotics...these patients will have untreatable infections.

What are the implications of finding Colistin resistance in Enterobacteriaceae?Over the past few years we have seen the emergence of carbapenem resistant Enterobacteriaceae (CRE) (see previous blog) and Colistin has become the mainstay of treatment for infections caused by these bacteria, usually combined with Tigecycline or Amikacin. Whilst Tigecycline resistance remains uncommon Tigecycline is a bacteriostatic agent which is not active in the urinary tract (a quarter of the Colistin resistant bacteria from humans in China were found in urine!). Amikacin resistance on the other hand has been widely described already.

So Colistin resistance due to the MCR-1 gene has effectively rendered infections caused by these bacteria impossible to treat (UTIs, hospital acquired pneumonias, diverticulitis, peritonitis, cholecystitis, sepsis, not to mention post operative infections). It was perhaps inevitable that this would happen, but even at my most cynical I thought it might take a few more years for transferable Colistin resistance to occur. It hasn’t, Colistin resistance in Enterobacteriaceae is already here and we have nothing left to treat these bacteria with.

So do you still think I’m being melodramatic when I say we have entered the post antibiotic era on 18th November 2015?!

Abdel-Halim Yousef

21/12/2015 03:14:59 pm

Hi
Thank you for this comprehensive piece. Still I have a question, is it mandatory for a bacterium which is colistin resistant to be resistant to ALL others? In other way why is it not possible that it has MCR-1 ONLY? Am I so silly?